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Introduction
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A major problem with cancer therapies is the low specificity of many treatment drugs. Conventional therapies are often administered in a systemic fashion, leading to numerous unwanted off-target effects. To mitigate such issues, there is thus a need for targeted drug delivery systems for anticancer drugs.
Bacteria have long been considered promising candidates for drug delivery. Some strains of bacteria are highly anaerobic, and can only survive in hypoxic environments. As the tumor microenvironment is one of the few few hypoxic sites in the human body. Anaerobic bacteria will therefore thrive in hypoxic tumour cores and die in oxygenated regions, allowing greater specificity in targeting. Clostridium novyi, an anaerobic bacterium, was found to successfully reduce tumour sizes in phase I clinical trials. However, Clostridium is relatively more difficult to manipulate than other strains of bacteria, making it an unideal choice of a delivery vector.
Besides strictly anaerobic microbes, there exist other bacteria strains which are facultative anaerobes, the most well-known being Escherichia coli. These strains can survive in both aerobic and anaerobic environments by changing their gene expression programmes accordingly. Thus, we can utilise the natural ability of E. coli to express certain genes under anaerobic conditions to express therapeutic genes/drugs only in the hypoxic core of the tumour.
However, the tumour core is not the only hypoxic location in the body. For example, the bone marrow and gut are also hypoxic environments in which the anaerobic expression programme may be activated. As a result, there is a need for more specific control of regulation of the therapeutic drugs or genes.
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The Quorum-Sensing System
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Quorum sensing (QS) is a system by which bacteria communicate with each other according to the density of the population. Through this system, bacteria are able to coordinate changes in gene expression and thereby alter their phenotype to better adapt to the environment. Our group aims to harness this system to regulate gene expression in our modified bacteria. As more bacteria gather in the hypoxic tumour core, they sense the increase in population density, and then express the gene of interest. Therefore, by placing the gene of interest under both hypoxic and QS regulation, we can precisely regulate the expression of the therapeutic drug or gene.
The esaR binding site however, would be our repressor site, where esaR will bind to when there’s no quorum sensing. esaR is a homologue of luxR. Unlike luxR which is activated upon binding to AHL, esaR loses its ability to bind on the binding site after forming a complex with AHL. Generally, esaR is paired with another protein - esaI. esaI synthesises AHL, which interferes the binding capabilities of esaR.
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